Process of producing pyrazinamide



United States Patent 2,705,714 PROCESS OF PRODUCING PYRAZINAMIDE John S.Webb and Herbert G. Arlt, Jr., Warren Township, Somerset County, N. J.,assignors to American Cyanamid Company, New York, N. Y., a corporationof Maine No Drawing. Application June 17, 1952, Serial No. 294,073

12 Claims. (Cl. 260-250) This invention relates paring pyrazinamide.Pyrazinamide has acquired considerable practical importance in recentyears by reason of its tuberculostatic activity. The processes ofproducing pyrazinamide have been cumbersome and have required a numberof steps to an improved process of pre- In general in the past, whenstarting with pyrazine2,3- dicarboxylic acid, the usual practicallyproducible intermediate, it has been necessary to decarboxylatepartially to pyrazinoic acid. This step has required considerable care,as high temperatures tend to carry the decarboxylation all the way topyrazine. After the pyrazinoic acid has been obtained, it wasesterified, usually with methyl alcohol, because the ordinary processesof amidation resulted in excessive losses due to decarboxylation topyrazine. The ester was then amidated by conventional In other words, inthe past it has been necessary to carry out three separate reactionsunder diiferent conditions and each resulting in a certain loss ofyield. As a result, the cost of pyrazinamide has been very high;

and its production has involved considerable operating In our copendingapplication Serial No. 294,072, filed June 17, 1952, we have describedand claimed an improved process of amidating pyrazinoic acid. In thisprocess, pyrazinoic acid or its ammonium salt is heated at hightemperature with urea. The urea stabilizes the pyrazinoic acid againstdecarboxylation and although the acid, Our improved process, however,from the fact necessary to prepare pyrazinoic acid or salt of pyrazinoicacid, and then to effect In other words, while we have reducedesterifying pyrazinoic acid, there is still required twoseparate stepsunder entirely different repyrazinamide are obtainable. referred toabove, still suffers, that it is first the ammonium action conditionsand without materially changing the time required for forming the amide.In other words, we can produce pyrazinamide frompyrazine-2,3-dicarboxylic acid or salts of 2,3-pyrazine-dicarboxylicacid, directly in a single step, in about the same time as re quired foramidating pyrazinoic acid. The exact mechanism of the present inventionis not known and it is present invention,

2,705,714 Patented .Apr. 5, 1955 alkali metal salt is transformed intothe corresponding ammonium salt.

The procedure of the reaction in the present invention is quite contraryto the normal behavior of urea with ortho-dibasic acids. Ordinarily,when ortho-dibasic acids are heated with urea, imides of the dibasicacid are formed. Thus, for example, when phthalic anhydride is heatedwith urea, there is formed first ortho-carboxy benzoyl urea or, if thetemperature is high enough, phthalimide. Ordinarily, this reactionmechanism with urea and ortho-dibasic acids results in the production ofthe most stable compound and hence is the only reaction which can benoted. Apparently, pyrazine-2,3-dicarboxylic acid behavesin a mediate,one would expect to obtain only the imide. However,pyrazine-Z,3-dicarboxylic acid does not form with urea the stable imidewhich ordinary ortho-dicarcorresponding monocarboxylic acid, pyrazinoicacid. The anomalous behavior of pyraz 1ne-2,3-d1carboxyl1c acid towardurea represents a is an extremely etficient single-step mediate step offorming pyrazinoic acid.

The amount of urea to be used is in no sense critical. Of course, enoughurea must be used to effect the amidation. In general, it is desirableto use amounts at least approximately equimolecular. Large excesses ofurea no harm; but neither do results and, therefore, while the inventionis not intended to be limited sons of economy.

The conditions of the reaction are not at all critical. The temperaturesin the reaction mixture itself may run from -190 or even 200 C. Whenbath-heated equipment is used, ordinarily the bath will. have to behigher and temperatures from ZOO-225 'C. are very satisfactory withequipment of ordinary heat transfer characteristics. While thetemperature is in no sense critical, we prefer to use temperatures whichwill result in sublimation of pyrazinamide. In other words, theequipment as a whole will operate under reflux. This permits recoveringa large portion of the pyrazinamide from the form of a solid sublimatewhich is relatively pure, containing no substantial gross impurities. Itis an advantage of the present invention that the temperature used is souncritical, since a very careful supervision or regulation of operatingconditions is entirely unnecessary, contributing therefore to smooth andsimple operation with a minimum of cost of supervision.

The time of the reaction will vary, not only with the temperature, butas is normal, with the size of the batch. It is, however, an advantagethat the time is not excessive and thus good outputs can be obtainedfrom a given piece of equipment. Reaction times of from to 6 or 8 hourswill give satisfactory results in suitable equipment. The invention,however, is in no sense limited to any time, the optimum time beingchosen in conjunction with the particular temperature used and the batchsize, equipment and other characteristics. It is, however, an advantagethat the heating time is not critical and, therefore, no controlproblems are involved.

It has been pointed out above that it is possible to use an alkali saltof pyrazine-2,3-dicarboxylic acid if there is present in the reactionmixture approximately equimolecular amounts of an ammonium salt such asammonium salt of a mineral acid. This constitutes a definite advantage,since very efiicient methods of preparation of the mono-potassium saltof pyrazine-2,3-dicarboxylic acid have been developed. The presentinvention is able to utilize this process and, therefore, even in theproduction of the pyrazinedicarboxylic acid, the most effective methodcan be used. However, of course, the invention is in no sense limited tothe method by which the pyrazine-2,3-dicarboxylic acid or its salts areprepared.

The invention will be described in greater detail in conjunction withthe specific examples, the parts being by weight unless otherwise noted.

Example 1 An equimolecular mixture of pyrazine-2,3-dicarboxylic acid andurea is introduced into a bath-heated reaction vessel, the bath beingmaintained at about 205210 C. As the charge heats up, the reactionmixture melts and begins to effervesce rapidly. After a while, theetTervescene slows down and the sublimate appears on the cooler part ofthe vessel. The temperature then is raised and the reaction is completedat a higher temperature. The heating for the final completion of thereaction may, for example, take from 1015 times as long as the heatingup during the effervescent stage.

After the reaction is substantially complete, the reaction vessel iscooled to room temperature and the sublimate removed. It constitutespyrazinamide of good quality, which can be transformed into apharmaceutical grade by, if desired, simple recrystallization.

Example 2 An equimolecular mixture of pyrazine-2,3-dicarboxylic acid andurea is introduced into a reaction vessel provided with a refluxcondenser. Ammonium hydroxide is then added to the reaction mixture inan amount approximately double that of the urea. The reaction mixtureheats up to 5060 C. and effervesces. Thereupon, the reaction vessel isheated and the mixture bubbles rapidly and liquid refluxes in thecondenser. After a short while, the reflux is terminated and the liquidis distilled out. Thereupon, the heating is continued until the reactionis substantially complete. As described in Example 1, sublimate isformed on the cooler parts of the reaction vessel and after completionof the reaction and cooling down of the vessel, the pyrazinamide isrecovered from the sublimate. If desired, the residue in the reactionvessel may be heated and some additional pyrazinamide is obtained bysublimation.

Example 3 A mixture of 84 parts (0.5 mol) pyrazine-2,3dicarboxylic acidwith 90 parts (1.5 mols) of urea is prepared. The mixture is added to areaction vessel containing 1950 parts of ortho-dichlorobenzene, thereaction vessel being equipped for agitation and reflux and the reactionvessel is heated and the reaction mixture refluxed under continuousagitation. The temperature is maintained until reaction is substantiallycomplete. At this point, the reaction mixture is a solution containingonly a small amount of solids. The hot liquid is decanted from thesolids, cooled to 5 C. and the pyrazinamide which crystallizes out isfiltered off.

Example 4 An equimolecular mixture of the mono-ammonium salt ofpyrazine-2,3-dicarboxylic acid and urea is introduced into the reactionvessel provided with a suitable condenser. The charge is graduallyheated up, melting starting at about 110 C. The heating is thenincreased and the temperature of the melt increases to about 160-165 C.,some sublimate being formed on the cooler portions of the reactionvessel. Finally, the reaction temperature is raised to about 188 C. andmaintained between this temperature and 195 C. until the reaction issubstantially complete. The mixture is then coole and the sublimateremoved. It constitutes pyrazinamide of good technical quality.

Example 5 215 parts of the mono-potassium salt of pyrazine-2,3-dicarboxylic acid hemihydrate, 180 parts of urea and 54 parts ofammonium chloride are intimately mixed and introduced into a reactionvessel equipped with a takeotf condenser and provided with an inlet forinert gas, so that it can be flushed. Heating is started, the mixturemelting almost at once to thick liquid which effervesces rapidly for ashort time. The melt then thickens, effervescence stops and a whitesublimate begins to form in the condenser. During these operations, thereaction mixture temperature has risen from C. to approximately C. Thebath temperature for heating the reaction vessel is then increasedsomewhat and a slow stream of nitrogen is passed continuously throughthe apparatus. The internal temperature of the reaction mixture rises toabout C. Finally, the bath temperature is increased somewhat and thereaction carried out to as near completion as possible. A Whitecrystalline material collects in the condenser and is removed. Itconstitutes pyrazinamide which can be purified by recrystallization fromalcohol, if desired.

We claim:

1. As a process of producing pyrazinamide from apyrazine-2,3-dicarboxylic acid compound having the formula o-o-x whereinX is a substituent selected from the class consisting of H and NH4, theprocess which comprises heating said pyrazine compound with urea untilpyrazinamide is formed and recovering the pyrazinamide so obtained.

2. A process according to claim 1 in which the proportions of saidpyrazine-2,3-dicarboxylic acid compound and urea are approximatelyequimolecular.

3. A process according to claim 2 in which the pyrazine-2,3-dicarboxylicacid compound is pyrazine-2,3- dicarboxylic acid.

4. A process according to claim 1 in which the pyrazine-2,3-dicarboxylicacid compound is pyrazine-2,3- dicarboxylic acid.

5. A process of producing pyrazinamide from the mono-ammonium salt ofpyrazine-2,3-dicarboxylic acid which comprises heating saidmono-ammonium salt with urea until pyrazinamide is formed and recoveringthe pyrazinamide so obtained.

6. A process according to claim 5 in which the amount of urea isapproximately equimolecular based on the mono-ammonium salt ofpyrazine-2,3-dicarboxylic acid.

7. The process of claim 5 wherein said mono-ammonium salt ofpyrazine-2,3-dicarboxylic acid is formed. in situ, in the reactionmixture from an alkali metal salt of pyrazine-2,3-dicarboxylic acidhaving the formula ie-mn N mono-ammonium salt thereof, continuing theheating until pyrazinamide is formed and recovering the pyrazinamide soobtained.

9. The process of claim 8 wherein the ammonium salt of the inorganicacid is ammonium chloride.

10. The process of claim 8 in which the amount of urea is approximatelyequimolecular based on the monopotassium salt ofpyrazine-2,3-dicarboxylic acid.

in which pyrazinamide is removed from the reaction mixture bysublimation.

12. A process as in claim 1 in which pyrazinamide is removed from thereaction mixture by flushing with an inert gas.

References Cited in the file of this patent UNITED STATES PATENTS OTHERREFERENCES Hall et al.: J. Am. Chem. Soc., 62, 664-665 (1940).

1. AS A PROCESS OF PRODUCING PYRAZINAMIDE FROM APYRAZINE-2,3-DICARBOXYLIC ACID COMPOUND HAVING THE FORMULA